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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq Bras Cardiol</journal-id>
      <journal-title-group>
        <journal-title>Arquivos Brasileiros de Cardiologia</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Arq. Bras. Cardiol.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">0066-782X</issn>
      <issn pub-type="epub">1678-4170</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">qL539FWzHVRV4qdLTQgSm5y</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2014002200012</article-id>
      <article-id pub-id-type="other">00012</article-id>
      <article-id pub-id-type="doi">10.5935/abc.20140153</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Letter to the Editor</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Immunopharmacological Approach of Carvedilol in Chronic Chagas Heart
               Disease</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Miranda</surname>
            <given-names>Carla Paix&#227;o</given-names>
          </name>
          <xref ref-type="aff" rid="aff01">1</xref>
          <xref ref-type="aff" rid="aff02">2</xref>
          <xref ref-type="corresp" rid="c01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Botoni</surname>
            <given-names>Fernando Ant&#244;nio</given-names>
          </name>
          <xref ref-type="aff" rid="aff01">1</xref>
          <xref ref-type="aff" rid="aff02">2</xref>
          <xref ref-type="aff" rid="aff03">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rocha</surname>
            <given-names>Manoel Ot&#225;vio da Costa</given-names>
          </name>
          <xref ref-type="aff" rid="aff01">1</xref>
          <xref ref-type="aff" rid="aff02">2</xref>
          <xref ref-type="aff" rid="aff03">3</xref>
        </contrib>
      </contrib-group>
      <aff id="aff01">
        <label>1</label>
        <institution content-type="orgname">Universidade Federal de Minas Gerais</institution>
        <addr-line>
          <named-content content-type="city">Belo Horizonte</named-content>
          <named-content content-type="state">MG</named-content>
        </addr-line>
        <institution content-type="original">Universidade Federal de Minas Gerais, Belo
               Horizonte, MG</institution>
      </aff>
      <aff id="aff02">
        <label>2</label>
        <institution content-type="orgname">Universidade Federal de Minas Gerais</institution>
        <institution content-type="orgdiv1">Escola de Medicina</institution>
        <institution content-type="orgdiv2">P&#243;s-Gradua&#231;&#227;o em Infectologia e Medicina
               Tropical</institution>
        <addr-line>
          <named-content content-type="city">Belo Horizonte</named-content>
          <named-content content-type="state">MG</named-content>
        </addr-line>
        <institution content-type="original">Universidade Federal de Minas Gerais, Escola de
               Medicina - P&#243;s-Gradua&#231;&#227;o em Infectologia e Medicina Tropical, Belo Horizonte,
               MG</institution>
      </aff>
      <aff id="aff03">
        <label>3</label>
        <institution content-type="orgname">Conselho Nacional de Desenvolvimento Cient&#237;fico e
               Tecnol&#243;gico</institution>
        <addr-line>
          <named-content content-type="city">Bras&#237;lia</named-content>
          <named-content content-type="state">DF</named-content>
        </addr-line>
        <institution content-type="original">CNPq - Conselho Nacional de Desenvolvimento
               Cient&#237;fico e Tecnol&#243;gico</institution>
      </aff>
      <author-notes>
        <corresp id="c01"><bold>Mailing Address: Carla Paix&#227;o Miranda,</bold> Rua Lindolfo
               Garcia, Alto do C&#243;rrego. Postal Code 38600-000, Paracatu, MG - Brazil. E-mail:
                  <email>carlanutribio@gmail.com</email>;
               <email>edmilsonbotelho@gmail.com</email></corresp>
      </author-notes>
      <pub-date pub-type="epub-ppub">
        <month>10</month>
        <year>2014</year>
      </pub-date>
      <volume>103</volume>
      <issue>4</issue>
      <fpage>358</fpage>
      <lpage>358</lpage>
      <history>
        <date date-type="received">
          <day>20</day>
          <month>06</month>
          <year>2014</year>
        </date>
        <date date-type="rev-recd">
          <day>15</day>
          <month>08</month>
          <year>2014</year>
        </date>
        <date date-type="accepted">
          <day>15</day>
          <month>08</month>
          <year>2014</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">
          <license-p>This is an Open Access article distributed under the terms of the Creative
                  Commons Attribution Non-Commercial License which permits unrestricted
                  non-commercial use, distribution, and reproduction in any medium, provided the
                  original work is properly cited.</license-p>
        </license>
      </permissions>
      <kwd-group xml:lang="en">
        <kwd>Chagas Cardiomyopathy</kwd>
        <kwd>Adenosine Desaminase/drug effects</kwd>
        <kwd>Antioxidants</kwd>
        <kwd>Drug-Related Side Effects and Adverses Reactions</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="0"/>
        <equation-count count="0"/>
        <ref-count count="4"/>
        <page-count count="1"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <p>
      <bold>Dear Editor,</bold>
    </p>
    <p>Evidence suggests that approximately 12 million individuals in Latin America are infected
         with <italic>Trypanosoma cruzi</italic> and present Chagas disease<xref ref-type="bibr" rid="B01">1</xref>. Even though the disease was described more than 100 years ago,
         chemotherapy directed against its etiological agent is restricted to two compounds which
         are only effective in the acute phase of the disease<xref ref-type="bibr" rid="B01">1</xref>, benznidazole and nifurtimox. Within this context, chronic Chagas heart
         disease (CHCD) lacks immunopharmacological studies, given that its pathogenesis involves an
         imbalance in the host's immune system. In the chronic phase, CHCD is associated with
         increased oxidative stress with intense and extensive inflammation and fibrosis in the
         myocardium, with consequent autonomic dysfunction and production of antibodies directed to
         the myocytes, beta adrenergic receptors, and neurons<xref ref-type="bibr" rid="B01">1</xref><sup>-</sup><xref ref-type="bibr" rid="B03">3</xref>. Rocha et al<xref ref-type="bibr" rid="B01">1</xref> demonstrate in their study that patients who develop
         CHCD present increased levels of TNF-alpha and CCL-2 when compared with individuals with
         the indeterminate form of Chagas disease<xref ref-type="bibr" rid="B01">1</xref>. A
         parallel then may be drawn with studies conducted by Yue et al. who reported that the
         production of superoxide anions occurs from activation of the NADPH system promoted by
         proinflammatory cytokines, in particular, TNF-alpha<xref ref-type="bibr" rid="B04">4</xref>. In fact, studies suggest that the antioxidant effects of carvedilol are very
         effective in the treatment of patients with CHCD. In addition to that, the presence of
         carbazole groups and hydroxylated metabolites in the molecular structure confers to
         carvedilol a high antioxidant activity<xref ref-type="bibr" rid="B02">2</xref><sup>,</sup><xref ref-type="bibr" rid="B03">3</xref>. Studies highlight the
         ability of carvedilol to act as a transition metal when donating electrons to reactive
         oxygen species (ROS) and reactive nitrogen species (RNS) in an attempt to neutralize the
         effects of oxidative damage caused by <italic>T. cruzi</italic> in the acute phase, which
         persist until the chronic phase<xref ref-type="bibr" rid="B04">4</xref>. Budni et al<xref ref-type="bibr" rid="B03">3</xref> in their study confirm this hypothesis showing that
         before a therapeutic intervention with carvedilol, patients with cardiac involvement showed
         high levels of oxidative markers, whereas patients who received an intervention with
         carvedilol showed increased levels of nitric oxide (NO) and adenosine deaminase (ADA),
         important supporting elements in oxidative defense and improvement of immune response<xref ref-type="bibr" rid="B03">3</xref><sup>,</sup><xref ref-type="bibr" rid="B04">4</xref>.
         Therefore, studies are needed to identify treatments able to prevent cardiac damage caused
         by this infection and to offer tools to improve survival and provide a better quality of
         life to affected individuals.</p>
  </body>
  <back>
    <ref-list>
      <title>References</title>
      <ref id="B01">
        <label>1</label>
        <mixed-citation>Rocha MOC, Ribeiro ALP, Teixeira MM. Clinical management of chronic
               Chagas cardiomyopathy. Front Biosci. 2003;8(1):44-54,</mixed-citation>
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            </name>
            <name>
              <surname>Ribeiro</surname>
              <given-names>ALP</given-names>
            </name>
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              <surname>Teixeira</surname>
              <given-names>MM</given-names>
            </name>
          </person-group>
          <article-title xml:lang="en">Clinical management of chronic Chagas
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          <source>Front Biosci</source>
          <year>2003</year>
          <volume>8</volume>
          <issue>1</issue>
          <fpage>44</fpage>
          <lpage>54</lpage>
        </element-citation>
      </ref>
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        <label>2</label>
        <mixed-citation>Botoni FA, Poole-Wilson PA, Ribeiro AL, Okonko DO, Oliveira BM, Pinto
               AS, et al. A randomized trial of carvedilol after renin-angiotensin system inhibition
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            <name>
              <surname>Botoni</surname>
              <given-names>FA</given-names>
            </name>
            <name>
              <surname>Poole-Wilson</surname>
              <given-names>PA</given-names>
            </name>
            <name>
              <surname>Ribeiro</surname>
              <given-names>AL</given-names>
            </name>
            <name>
              <surname>Okonko</surname>
              <given-names>DO</given-names>
            </name>
            <name>
              <surname>Oliveira</surname>
              <given-names>BM</given-names>
            </name>
            <name>
              <surname>Pinto</surname>
              <given-names>AS</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">A randomized trial of carvedilol after renin-angiotensin
                  system inhibition in chronic Chagas cardiomyopathy</article-title>
          <source>Am Heart J</source>
          <year>2007</year>
          <volume>153</volume>
          <issue>4</issue>
          <fpage>544</fpage>
          <lpage>548</lpage>
        </element-citation>
      </ref>
      <ref id="B03">
        <label>3</label>
        <mixed-citation>Budni P, Pedrosa RC, Garlet TR, Dalmarco EM, Lino MR, Simionato EL, et
               al. Carvedilol attenuates oxidative stress in chronic Chagasic cardiomyopathy. Arq
               Bras Cardiol. 2012;98(3):218-24.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Budni</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Pedrosa</surname>
              <given-names>RC</given-names>
            </name>
            <name>
              <surname>Garlet</surname>
              <given-names>TR</given-names>
            </name>
            <name>
              <surname>Dalmarco</surname>
              <given-names>EM</given-names>
            </name>
            <name>
              <surname>Lino</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Simionato</surname>
              <given-names>EL</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Carvedilol attenuates oxidative stress in chronic
                  Chagasic cardiomyopathy</article-title>
          <source>Arq Bras Cardiol</source>
          <year>2012</year>
          <volume>98</volume>
          <issue>3</issue>
          <fpage>218</fpage>
          <lpage>224</lpage>
        </element-citation>
      </ref>
      <ref id="B04">
        <label>4</label>
        <mixed-citation>Yue TL, Cheng HY, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, et al.
               Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and
               free radical scavenger. J Pharmacol Exp Ther. 1992;263(1):92-8.</mixed-citation>
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Yue</surname>
              <given-names>TL</given-names>
            </name>
            <name>
              <surname>Cheng</surname>
              <given-names>HY</given-names>
            </name>
            <name>
              <surname>Lysko</surname>
              <given-names>PG</given-names>
            </name>
            <name>
              <surname>McKenna</surname>
              <given-names>PJ</given-names>
            </name>
            <name>
              <surname>Feuerstein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Gu</surname>
              <given-names>JL</given-names>
            </name>
            <etal>et al</etal>
          </person-group>
          <article-title xml:lang="en">Carvedilol, a new vasodilator and beta adrenoceptor
                  antagonist, is an antioxidant and free radical scavenger</article-title>
          <source>J Pharmacol Exp Ther</source>
          <year>1992</year>
          <volume>263</volume>
          <issue>1</issue>
          <fpage>92</fpage>
          <lpage>98</lpage>
        </element-citation>
      </ref>
    </ref-list>
  </back>
  <sub-article article-type="translation" id="SA1" xml:lang="pt">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Carta ao Editor</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Abordagem Imunofarmacol&#243;gica do Carvedilol na Cardiomiopatia Chag&#225;sica
               Cr&#244;nica</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Miranda</surname>
            <given-names>Carla Paix&#227;o</given-names>
          </name>
          <xref ref-type="aff" rid="aff04">1</xref>
          <xref ref-type="aff" rid="aff05">2</xref>
          <xref ref-type="corresp" rid="c02"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Botoni</surname>
            <given-names>Fernando Ant&#244;nio</given-names>
          </name>
          <xref ref-type="aff" rid="aff04">1</xref>
          <xref ref-type="aff" rid="aff05">2</xref>
          <xref ref-type="aff" rid="aff06">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rocha</surname>
            <given-names>Manoel Ot&#225;vio da Costa</given-names>
          </name>
          <xref ref-type="aff" rid="aff04">1</xref>
          <xref ref-type="aff" rid="aff05">2</xref>
          <xref ref-type="aff" rid="aff06">3</xref>
        </contrib>
      </contrib-group>
      <aff id="aff04">
        <label>1</label>
        <institution content-type="orgname">Universidade Federal de Minas Gerais</institution>
        <addr-line>
          <named-content content-type="city">Belo Horizonte</named-content>
          <named-content content-type="state">MG</named-content>
        </addr-line>
        <institution content-type="original">Universidade Federal de Minas Gerais, Belo
               Horizonte, MG</institution>
      </aff>
      <aff id="aff05">
        <label>2</label>
        <institution content-type="orgname">Universidade Federal de Minas Gerais</institution>
        <institution content-type="orgdiv1">Escola de Medicina</institution>
        <institution content-type="orgdiv2">P&#243;s-Gradua&#231;&#227;o em Infectologia e Medicina
               Tropical</institution>
        <addr-line>
          <named-content content-type="city">Belo Horizonte</named-content>
          <named-content content-type="state">MG</named-content>
        </addr-line>
        <institution content-type="original">Universidade Federal de Minas Gerais, Escola de
               Medicina - P&#243;s-Gradua&#231;&#227;o em Infectologia e Medicina Tropical, Belo Horizonte,
               MG</institution>
      </aff>
      <aff id="aff06">
        <label>3</label>
        <institution content-type="orgname">Conselho Nacional de Desenvolvimento Cient&#237;fico e
               Tecnol&#243;gico</institution>
        <addr-line>
          <named-content content-type="city">Bras&#237;lia</named-content>
          <named-content content-type="state">DF</named-content>
        </addr-line>
        <institution content-type="original">CNPq - Conselho Nacional de Desenvolvimento
               Cient&#237;fico e Tecnol&#243;gico. Bras&#237;lia, DF, Brasil</institution>
      </aff>
      <author-notes>
        <corresp id="c02"><bold>Correspond&#234;ncia: Carla Paix&#227;o Miranda,</bold> Rua Lindolfo Garcia, Alto do
               C&#243;rrego. CEP 38600-000, Paracatu, MG - Brasil. E-mail:
                  <email>carlanutribio@gmail.com</email>; <email>edmilsonbotelho@gmail.com</email>
            </corresp>
      </author-notes>
      <kwd-group xml:lang="pt">
        <kwd>Cardiomiopatia Chag&#225;sica</kwd>
        <kwd>Adenosina Desaminase/efeitos de drogas</kwd>
        <kwd>Antioxidantes</kwd>
        <kwd>Efeitos Colaterais e Rea&#231;&#245;es Adversas Relacionados a Medicamentos</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <p>
        <bold>Prezado Editor,</bold>
      </p>
      <p>Dados indicam que aproximadamente 12 milh&#245;es de indiv&#237;duos na Am&#233;rica Latina estejam
            infectados com o <italic>Trypanosoma cruzi</italic>, apresentando a doen&#231;a de
               Chagas<xref ref-type="bibr" rid="B01">1</xref>. Embora a doen&#231;a tenha sido descrita
            h&#225; mais de 100 anos, a quimioterapia contra seu agente etiol&#243;gico se resume a dois
            compostos efetivos apenas na fase aguda da doen&#231;a<xref ref-type="bibr" rid="B01">1</xref>: benzonidazol e nifurtimox. Neste contexto, a cardiopatia chag&#225;sica cr&#244;nica
            (CCC) carece dfe estudos a n&#237;vel imunofarmacol&#243;gico, tendo em vista que a sua patog&#234;nese
            envolve um desequil&#237;brio no sistema imunol&#243;gico do hospedeiro. Na fase cr&#244;nica, a CCC
            apresenta aumento do estresse oxidativo com intensa e extensa inflama&#231;&#227;o e fibrose no
            mioc&#225;rdio, com consequente disfun&#231;&#227;o auton&#244;mica e produ&#231;&#227;o de anticorpos dirigidos aos
            mi&#243;citos, receptores beta adren&#233;rgicos e neur&#244;nios<xref ref-type="bibr" rid="B01">1</xref><sup>-</sup><xref ref-type="bibr" rid="B03">3</xref>. Rocha e cols.<xref ref-type="bibr" rid="B01">1</xref> mostram em seu estudo que pacientes que
            desenvolvem a CCC apresentam n&#237;veis aumentados de TNF-alfa e CCL-2 quando comparados a
            indiv&#237;duos com a forma indeterminada da doen&#231;a de Chagas<xref ref-type="bibr" rid="B01">1</xref>. Um paralelo pode ent&#227;o ser tra&#231;ado com estudos realizados por Yue e
               cols.<xref ref-type="bibr" rid="B04">4</xref> que mostram que a produ&#231;&#227;o de &#226;nions
            super&#243;xidos se faz a partir da ativa&#231;&#227;o do sistema NADPH promovida por citocinas
            pr&#243;-inflamat&#243;rias, especificamente o TNF-alfa<xref ref-type="bibr" rid="B04">4</xref>.
            De fato, estudos sugerem que os efeitos antioxidantes do carvedilol s&#227;o bastante
            efetivos na terap&#234;utica de pacientes com CCC. Al&#233;m disto, a presen&#231;a de grupos carbazol
            e metab&#243;litos hidroxilados na estrutura molecular conferem alta atividade antioxidante
            ao carvedilol<xref ref-type="bibr" rid="B02">2</xref><sup>,</sup><xref ref-type="bibr" rid="B03">3</xref>. Estudos acentuam a capacidade do carvedilol em atuar como metal
            de transi&#231;&#227;o na doa&#231;&#227;o de el&#233;trons para esp&#233;cies reativas de oxig&#234;nio (ROS), bem como
            para esp&#233;cies reativas de nitrog&#234;nio (RNS), na tentativa de neutralizar os efeitos dos
            danos oxidativos causado pelo <italic>T. cruzi</italic> na fase aguda, mas que
            repercutem at&#233; a fase cr&#244;nica<xref ref-type="bibr" rid="B04">4</xref>. Budni e
               cols.<xref ref-type="bibr" rid="B03">3</xref> no seu estudo confirmam esta hip&#243;tese.
            Nele, os autores mostram que antes de uma interven&#231;&#227;o terap&#234;utica com carvedilol,
            pacientes com comprometimento card&#237;aco apresentaram altos n&#237;veis de marcadores
            oxidativos enquanto que os pacientes que receberam a interven&#231;&#227;o com o carvedilol
            apresentaram aumento nos n&#237;veis de &#243;xido n&#237;trico (NO) e adenosina deaminase (ADA),
            importantes elementos coadjuvantes na defesa oxidativa e na melhora da resposta
               imune<xref ref-type="bibr" rid="B03">3</xref><sup>,</sup><xref ref-type="bibr" rid="B04">4</xref>. Portanto, estudos ser&#227;o necess&#225;rios para identificar tratamentos
            capazes de prevenir os danos card&#237;acos causados por essa infec&#231;&#227;o e fornecer ferramentas
            para melhorar a sobrevida e proporcionar uma melhor qualidade de vida aos indiv&#237;duos
            afetados.</p>
    </body>
  </sub-article>
</article>
